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Neurotoxicity of Penicillium crustosum secondary metabolites: tremorgenic activity of orally administered penitrem A and thomitrem A and E in mice.

Abstract
Several cases of neurological disease in dogs after poisoning by food- and feed-borne Penicillium toxins in Norway during the last years have uncovered a lack of knowledge regarding the toxicity and mechanism of action of neuroactive mycotoxins. In the present study, the lowest tremor-inducing dose after single oral administration of penitrem A to mice was 0.50 mg/kg bw. The estimated half maximal effective dose (ED(50)) in respect to the visual tremor scale was 2.74 mg/kg bw. Mice receiving the maximum penitrem A dose (8 mg/kg bw) suffered severe spontaneous tremors and even convulsions. Thomitrem A and E are penitrem analogues lacking the C-16-C-18 ether linkage and possessing an olefin at C-18-C-19. Compared with penitrem A, the lowest tremor-inducing dose of thomitrem A was 16-times higher (8 mg/kg bw) and thomitrem E was found to be non-tremorgenic at the highest dose tested (16 mg/kg bw). During a recovery phase of two weeks post administration animals appeared restored and no changes in feeding and other biological processes were observed. An initial dose-related weight reduction was observed 2 days after penitrem A administration. Penitrem A was absorbed and distributed to gastrointestinal tract, liver, kidneys and brain in the mice. Elimination of penitrem A appeared to be mainly hepatic and the highest concentration levels were found 1 h post administration for all investigated organs. The relationship between liver and gastrointestinal tract concentration levels showed time-dependent linear correlation and a doubling within 1.5 h.
AuthorsAngel Moldes-Anaya, Thomas Rundberget, Christiane K Fæste, Gunnar S Eriksen, Aksel Bernhoft
JournalToxicon : official journal of the International Society on Toxinology (Toxicon) Vol. 60 Issue 8 Pg. 1428-35 (Dec 15 2012) ISSN: 1879-3150 [Electronic] England
PMID23085423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Indoles
  • Mycotoxins
  • thomitrem A
  • thomitrem E
  • tremortin
Topics
  • Administration, Oral
  • Animals
  • Chromatography, High Pressure Liquid
  • Indoles (administration & dosage, toxicity)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mycotoxins (administration & dosage, toxicity)
  • Penicillium (metabolism)
  • Tandem Mass Spectrometry
  • Tremor (chemically induced)

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